1. Field of the Invention
This invention relates to a method for resisting damage to brain cells resulting from excess stimulation of the NMDA receptors thereof by glutamate and, more specifically, it relates to a method for accomplishing this in vivo without exposing the subject to meaningful untoward side effects.
2. Description of the Prior Art
Neurodegenerative disorders such as stroke (ischemia), for example, may cause death or permanent impairment. Progressive nerve cell impairment may be caused by a number of means including ischemia, anoxia, trauma, and exposure to environmental or occupational neurotoxic agents.
Nerve cells in the human brain communicate with each other through chemical signals. The excitatory chemical signal is effected by release of glutamate, which is an amino acid. The cells receiving these signals have receptors. With respect to glutamate, such cells have three main types of excitatory amino acid receptors. These are kainate, quisqualate, and N-Methyl-D-Aspartate (NMDA). Excess quantities of glutamate are potentially toxic to such nerve receptors and can damage the same. It has been found that in certain conditions such as ischemia, nerve cells die because of overstimulation by glutamate of the NMDA receptors. (These receptors are known as "NMDA receptors" as N-Methyl-D-Aspartate is a more effective agonist in this particular glutamate receptor at the other types of glutamate receptors). An analysis of the origin of ischemia-induced glutamate release from brain tissue is contained in Drejer, et al Journal of Neurochemistry, Vol. 45, Pages 145-151 (1985).
In this situation, the glutamate is considered an agonist, i.e., a material that can directly activate a receptor. It has been known to use antagonists to counteract the effect of an agonist on a nerve cell receptor. In essence, the antagonists may be considered as binding to the receptor and displacing the agonist thereby resisting the undesired damage. See generally, co-pending United States patent application Ser. No. 395,396, filed Aug. 17, 1989 and Simon et al. Science 226:850-852 (1984), Gill et al J. Neuroscience 7: 3343-3349 (1987), Andine et al. Neuroscience Letter 90:208-212 (1988), Kochhar et al. Arch. Neurol. 45:148-153 (1988).
It has previously been suggested that overstimulation of the NMDA receptors may cause nerve cell death in heart attack or stroke patients. See Barnes, Science Vol. 239 pp. 254-256 (1988). See also Hahn et al., Science USA, 85:6556 (1988).
In respect of the abnormal activation of glutamate receptors specific for the synthetic analogue, NMDA has been indicated as contributing to progressive neurodegenerative disorders. See Choi et al., Neuron, Vol. 1, Pages 623-634 (1988); Choi et al., The Journal of Neuroscience, 7(2):Pages 357-368 (1985); and Choi et al. The Journal of Neuroscience 8(1):Pages 185-196 (1988).
U.S. Pat. No. 4,806,543 discloses a method of reducing adverse effects of neurotoxic injury by administering an enantiomer of an analgesic opioid agonist or antagonist. The compounds are said to be useful for treatment of animal species having NMDA receptors.
It has been suggested that selected antagonism of NMDA receptors can reduce hypoxic ischemic neuronal injury. See Steinberg et al., Stroke, Vol. 20., No. 9, Page 1247-1252 (1989).
Co-pending United States patent application Ser. No. 395,396 discloses a class of simple amino acids which are derivatives of topa quinone, a potent glutamate agonist acting at non-NMDA (i.e., kainate or quisqualate) receptors. Topa quinone was found to be a good oxidizing agent acting at NMDA receptor redox modulatory sites. Topa quinone, however, is neurotoxic and it is highly unstable in solution.
Among such suggested materials are magnesium (Nowack et al. Nature 307:462-564 (1984)); glycine (Johnson et al. Nature 325:529-531 (1987)); zinc (Westbrook et al. Nature 328:640-643 (1987)); (Peters et al. Science 236:589-593 (1987)); and polyamines, (Ransom et al. J. Neurochem. 51:830-836 (1988)). See also the reference to use of phencyclidine and ketamine, as well as 2-amino-7 phosphonohep tanoic acid (AP7) all suggested as NMDA receptor specific antagonists in Mayer et al. Tins Pages 59-61 (1987).
It is also been suggested that the drug (+-5-methyl-10, 11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine maleate (MK-801) may provide neuroprotective effects in respect of the NMDA receptors. See Gill et al., Neuroscience, Vol. 25, No. 3, Pages 847-855 (1988).
It is also been known that traumatic neuronal injury may contribute to neuronal degeneration which may be reduced by an NMDA antagonist. See Tecoma et al., Neuron, Vol. 2, Pages 1541-1545 (1989).
Modulation of NMDA responses by reduction and oxidation as by using sulfhydryl redox reagents dithiothreitol (DTT) and 5-5-dithio-bis-2-nitrobenzoic acid (DTNB) NMDA responses has been considered in Aizenman et al. Neuron, Vol. 2, Pages 1257-1263 (1989). Regulation of NMDA function by reduction or oxidation is suggested.
In spite of the recognition of the problem and efforts to employ means to block the consequences of abnormal activation of glutamate on NMDA, there remains a very real and substantial need for an improved method for both preventative measures and therapeutic measures so as to resist the adverse consequences of neurodegenerative disorders.